From the Masseuse to the Nociceptor

From the Masseuse to the Nociceptor

Randomized trials have shown that massage can ease low back and neck pain, but the cellular and molecular basis for this benefit has remained unclear—until now. In clinical research examining the effects of massage on exercise-induced muscle damage, Mark Tarnopolsky, from McMaster University in Hamilton, Ontario, Canada, along with colleagues demonstrate that massage reduces levels of inflammatory cytokines known to activate peripheral nociceptors and produce hyperalgesia.

Though the authors do not make any direct comparisons, they suggest that massage may reduce pain in a manner similar to that of non-steroidal anti-inflammatory drugs, and may even have some advantages over the latter. “From a pain reduction perspective, it is likely that the two are fairly comparable,” wrote Tarnopolsky in a prepared statement about the work. “It is unclear if there are any side effects from a massage, but on balance it is likely that they would be less than the known side effects from anti-inflammatories leading to gastrointestinal upset,” he said. While the current work is entirely preliminary, it begins to suggest that massage could one day become another important tool, undergirded by a sound scientific rationale, in the physician’s pain-reducing armamentarium.

The new findings were published in the February 1 issue of Science Translational Medicine.

Microarrays point the way towards a mechanism

Massage therapy is a common form of alternative medicine sought by 18 million people each year, just in the United States alone, to relieve pain and disability. A recent systematic review and meta-analysis of massage therapy suggests they are wise to do so, as it substantiates the effectiveness of massage to alleviate acute and chronic low back and neck pain (Furlan et al., 2011). Nonetheless, despite massage’s popularity and effectiveness for pain, its cellular and molecular underpinnings are murky.

In the current study, Tarnopolsky and coworkers subjected 11 young males to a bout of intense aerobic exercise on an upright bicycle. After exercise, subjects received a 10-minute massage on one outer thigh and no treatment on the other, enabling each subject to serve as his own control. Muscle biopsies were taken at baseline, immediately after the massage, and after a 2.5-hour recovery period.

Results from cDNA microarray analyses revealed variations in messenger RNA levels indicative of increased production of new mitochondria and decreased inflammation. These findings led the investigators to examine the effects of massage on particular proteins known to play roles in those processes. What they discovered supported the microarray findings and provided the first credible mechanistic explanation of massage’s beneficial effect on pain.

First, the researchers found increased nuclear levels of peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), a protein that helps to make new mitochondria, in massaged legs 2.5 hours after treatment, compared to untreated legs. Next, activation of proteins upstream from PGC-1α in massaged legs, as well as increased levels of downstream targets, further indicated that massage’s therapeutic benefits lie in the mitochondrial realm.

However, Tarnopolsky and colleagues found that the benefit of massage was as much of an inflammation and pain story as a mitochondrial tale. Indeed, they observed decreased levels of nuclear factor kB (NFkB), a regulatory protein that mediates inflammation, immediately after massage, as well as decreased activity of HSP27, a heat shock protein that sits downstream of NFkB, at the 2.5-hour mark. In terms of downstream effects of NFkB, the observation of decreased levels of the inflammatory cytokine interleukin-6 (IL-6) at 2.5 hours, as well as a decrease in the ratio of mature tumor necrosis factor-α, another inflammatory cytokine, to the precursor form immediately after massage, further suggested that massage’s therapeutic effects are linked to molecules that mediate inflammation and pain.

The need for caution

Not only does the current study offer a plausible explanation for positive findings from recent clinical trials examining the effects of massage on back and cancer bone pain (Cherkin et al., 2011 and Jane et al., 2011), but it is also consistent with recent preclinical work linking massage to inflammation reduction. For instance, a study using a mouse inflammation model revealed that in-vivo tissue stretch of the low back reduced inflammation-induced effects such as altered gait, local mechanical sensitivity, and macrophage infiltration of connective tissues (Corey et al., 2012). However, while it is exciting to see the current work translate such findings into a clinical setting, several important caveats are in order.

One shortcoming is that, of the entire population of massage-seekers, the study examined only a small subgroup, and just one massage protocol, making the relevance of the findings to chronic pain unclear. “The applicability of these results may be limited to healthy, young subjects receiving a short-term single session of massage and may not be extrapolated to healthy but older subjects, to those receiving repeated sessions of massage over the long term, or to subjects of any age diagnosed with a clinical condition,” said Alexander Tsertsvadze of the Ottawa Hospital Research Institute in Canada and a coauthor of the recent systematic review and meta-analysis, who was not involved with the current study.

Another weakness is the time frame of the study, which focused solely on effects observed at 10 minutes and 2.5 hours post-massage. “Since inflammation is usually maximal 24 to 48 hours following high-intensity exercise, clearly the next step would be to determine whether the actual inflammatory response 24 to 48 hours following unaccustomed or very high-intensity exercise is attenuated [by massage], and whether this leads to a more rapid recovery,” Tarnopolsky cautioned in his prepared statement. Finally, the author also points out that inflammation may actually allow muscles to heal after they are damaged, so any strategy based on reducing inflammation must be careful not to interfere with the natural healing process.

Still, the current investigation suggests that when the masseuse’s hands touch the muscles and ease pain, there is compelling science to explain the benefit.

Karl Gruber is a Ph.D. candidate in Genetics at Heinrich Heine University in Düsseldorf, Germany, and a freelance science writer.